Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
1.
Ann Oncol ; 27(3): 519-25, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26759276

RESUMEN

BACKGROUND: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta-analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety. PATIENTS AND METHODS: Data were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately. RESULTS: The rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62-1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66-1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)]. CONCLUSIONS: Stomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines.


Asunto(s)
Antineoplásicos/efectos adversos , Everolimus/efectos adversos , Inmunosupresores/efectos adversos , Membrana Mucosa/patología , Estomatitis/inducido químicamente , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Supervivencia sin Enfermedad , Everolimus/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Neoplasias/tratamiento farmacológico , Estomatitis/epidemiología , Esclerosis Tuberosa/tratamiento farmacológico
2.
ESMO Open ; 6(4): 100226, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34371379

RESUMEN

BACKGROUND: Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) and disease-related poor prognostic factors are not well characterized. We aimed to describe patient demographics, disease characteristics, treatment patterns and patient-reported outcomes in a subset of HR+/HER2- ABC patients with these factors [at the time when cyclin-dependent kinase (CDK) 4 and 6 inhibitors were being introduced] and understand how these factors informed treatment decisions at the time of the survey. METHODS: Real-world data were derived from a large, multinational, point-in-time survey of oncologists and their consulting patients with HR+/HER2- ABC in the EU5 and USA over March-June 2017, at the start of the changing treatment landscape. Analysis focused on four poor prognostic factors: visceral metastases, liver metastases (subset of visceral metastases), progesterone receptor-negative status and high tumor grade. RESULTS: In total, 2259 patients with HR+/HER2- ABC had records eligible for this analysis. At least one poor prognostic factor was present in 63% of patients (most common visceral metastases; least common progesterone receptor-negative status), with varying degrees of overlap between factors. For physician-reported outcomes, pain increased, whereas performance status and activities of daily living declined with presence of poor prognostic factors, especially liver metastases. No clear trends were observed for patient-reported outcomes. Treatment with combined endocrine therapy plus CDK4 and 6 inhibitors was infrequent, as these agents were entering the market. CONCLUSIONS: More than 60% of the HR+/HER2- ABC Adelphi Real World Disease Specific Programme™ sample had ≥1 disease-related poor prognostic factor, and patients appeared to be heterogeneous regarding occurrence and distribution of these factors. These patients typically have increased pain and reduced performance status, highlighting the importance of implementing effective therapy with CDK4 and 6 inhibitors. Future studies could inform how the treatment landscape has evolved over time with respect to patients with poor prognostic factors.


Asunto(s)
Neoplasias de la Mama , Actividades Cotidianas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/epidemiología , Femenino , Humanos , Medición de Resultados Informados por el Paciente , Pronóstico , Receptor ErbB-2/uso terapéutico , Receptores de Estrógenos/uso terapéutico
3.
J Mol Biol ; 266(2): 231-45, 1997 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-9047360

RESUMEN

Hepatocyte nuclear factor 1 (HNF1) is a dimeric homeoprotein expressed in hepatocytes and in a few other epithelial cells where it helps regulate the expression of a specific subset of genes. In an attempt to identify novel target genes for HNF1 and to assess the distribution of its target sites within the vertebrate genome, we performed a computer-assisted search within the available databases using a weighted matrix. Several hundred potential target sequences were identified within the GenBank and EMBL data banks. DNA binding assays demonstrated that more than 95%, of the new sites tested (52 sites among 54) bound HNF1. Surprisingly many HNF1 target sites were found in genes that are transcribed in cell types that do not contain the protein. On the other hand these sites are 2.5 to five times more frequent in hepatic genes than expected. It seems that the presence of HNF1 sites in liver-specific genes was favoured, but that no counter-selection occurred within the rest of the genome. HNF1 binding sites in liver genes are more often associated in clusters with sites for other transcription factors and the enrichment is more pronounced in promoter regions. We identified more than 100 liver specific genes that are potentially regulated by HNF1.


Asunto(s)
Proteínas de Unión al ADN , ADN/metabolismo , Proteínas Nucleares , Alineación de Secuencia/métodos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Vertebrados/genética , Animales , Sitios de Unión , Unión Competitiva , Bases de Datos Factuales , Elementos de Facilitación Genéticos , Genoma , Factor Nuclear 1 del Hepatocito , Factor Nuclear 1-alfa del Hepatocito , Factor Nuclear 1-beta del Hepatocito , Humanos , Hígado/fisiología , Familia de Multigenes , Oligonucleótidos/química , Oligonucleótidos/metabolismo , Regiones Promotoras Genéticas
5.
Phys Rev B Condens Matter ; 39(12): 8768-8771, 1989 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-9947602
8.
J Biol Chem ; 268(34): 25706-11, 1993 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-8245006

RESUMEN

Two forms of the transcription factor vHNF1 (HNF1 beta or LFB3) have been previously described, derived by alternative splicing from a common premessenger RNA, and have been called vHNF1-A and vHNF1-B. vHNF1 proteins share a homologous homeo-related DNA-binding domain with the HNF1 protein, initially characterized as a liver-restricted transcription factor, and bind to a similar sequence motif. Here we demonstrate that vHNF1-A is a stronger transactivator than vHNF1-B when assayed in transient transfections using two different promoters. vHNF1-A also binds DNA with a higher affinity suggesting that a region of the protein located immediately upstream of the homeodomain can modulate the protein/DNA interaction and transactivation. Both vHNF1 transcripts were found at a constant ratio in every tissue where vHNF1 expression could be detected, using a quantitative reverse transcriptase-polymerase chain reaction.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Unión Competitiva , Línea Celular , Cartilla de ADN , Proteínas de Unión al ADN/biosíntesis , Femenino , Variación Genética , Factor Nuclear 1 del Hepatocito , Factor Nuclear 1-alfa del Hepatocito , Factor Nuclear 1-beta del Hepatocito , Humanos , Cinética , Sustancias Macromoleculares , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos/metabolismo , Oligodesoxirribonucleótidos/farmacología , Especificidad de Órganos , Reacción en Cadena de la Polimerasa , Ratas , Factores de Transcripción/biosíntesis , Transcripción Genética , Transfección , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino
9.
J Virol ; 72(2): 1616-22, 1998 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9445066

RESUMEN

We have characterized a major regulatory element of ground squirrel hepatitis virus (GSHV) located within a 90-nucleotide fragment of the core promoter upstream sequences and have compared its organization to that of woodchuck hepatitis virus (WHV) enhancer II (We2). The GSHV element (Ge2) stimulates transcription from the viral core promoter and heterologous promoters in an orientation-independent manner but displays a lower level of activity than We2 in transient transfection assays in human hepatoma cells. The general organization of Ge2 into binding sites for the liver-enriched HNF-1 and HNF-4 proteins and for ubiquitous factors of the NF1 and Oct families was found to be mostly conserved with respect to the homologous We2 region. Accordingly, transactivation by HNF-1 and HNF-4 plays an essential role in the liver-specific transcriptional activity of both the GSHV and WHV core promoters. Distinctive features of the GSHV enhancer consist of its ability to bind C/EBP family factors in a central motif that overlaps with one of the two HNF-4 sites and its differential binding affinities for HNF-4.


Asunto(s)
Elementos de Facilitación Genéticos/genética , Orthohepadnavirus/genética , Animales , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Proteínas del Núcleo Viral/genética
10.
J Virol ; 70(12): 8571-83, 1996 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8970982

RESUMEN

Transcriptional activation of myc family proto-oncogenes through the insertion of viral sequences is the predominant mechanism by which woodchuck hepatitis virus (WHV) induces liver tumors in chronically infected animals. The main target is N-myc2, a functional retroposon of the N-myc gene, but c-myc and N-myc are also marginally involved. Here we identify a major, liver-specific regulatory element in the WHV genome (We2) which efficiently activates the N-myc2 promoter in cultured hepatoma cells. In the context of the episomal viral genome, We2 governs the production of pregenomic RNA and thus plays a central role in the control of viral replication. We2 activity is primarily controlled by the liver-enriched HNF1 and HNF4 transcription factors, although NF1 and Oct proteins were also shown to bind in a central region. The expression of HNF1 and HNF4 appears to be maintained in woodchuck tumors. Thus, We2 is a prime candidate for controlling myc gene cis activation during WHV-induced hepatocarcinogenesis.


Asunto(s)
Proteínas de Unión al ADN , Virus de la Hepatitis B de la Marmota/genética , Proteínas Nucleares , Fosfoproteínas/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-myc/genética , Secuencias Reguladoras de Ácidos Nucleicos , Retroelementos , Factores de Transcripción/metabolismo , Activación Transcripcional , Animales , Secuencia de Bases , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Sitios de Unión , ADN Viral , Antígenos del Núcleo de la Hepatitis B/genética , Virus de la Hepatitis B de la Marmota/fisiología , Factor Nuclear 1 del Hepatocito , Factor Nuclear 1-alfa del Hepatocito , Factor Nuclear 1-beta del Hepatocito , Factor Nuclear 4 del Hepatocito , Humanos , Hígado , Datos de Secuencia Molecular , ARN , Conejos , Células Tumorales Cultivadas , Replicación Viral
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA